Companies
have developed recombinant TRAIL derivatives and antibodies targeting DR4 or
DR5 to selectively induce apoptosis in tumor cells. However, none of those
approaches has advanced into Phase III testing due to poor efficacy.2,3

The
Penn State researchers took a fresh approach to modulating the TRAIL pathway by
screening for small molecule inducers of TRAIL expression. Corresponding author
Wafik El-Deiry told SciBX that his team hypothesized that small
molecules could be more efficacious than biologics because their superior
bioavailability and biodistribution properties would induce high levels of
TRAIL in cells throughout the tumor and its surrounding microenvironment.

El-Deiry
is professor of medicine and chief of hematology and oncology at the medical
center.

The
team used a cell-based reporter assay to screen a National Cancer Institute library of about
2,000 compounds for their ability to induce TRAIL expression. The screen
identified a small molecule, dubbed TRAIL-inducing
compound 10 (TIC10), which led to
TRAIL mRNA and protein expression in a panel of cancer cell lines and triggered
TRAIL-dependent cell death at low micromolar concentrations. In mice, the same
molecule induced TRAIL expression in tissues including the brain, kidney
and spleen.

The
next step was to evaluate the efficacy of TIC10 in a series of mouse models for
cancer.

In
xenograft mice bearing breast or colon cancer cell lines, injection of TIC10
decreased tumor growth compared with vehicle control injection, and its
effectiveness was equal or superior to that of recombinant TRAIL. Oral
dosing of the compound at 25 mg/kg also decreased tumor growth compared with
vehicle dosing.

Penn State has
exclusively licensed the findings to Oncoceutics, for which El-Deiry is
cofounder and CSO. The company was founded in 2009 to develop small molecules
with activity against p53-deficient
cancers.

TIC10
was effective against both p53-wild-type and p53-mutant cells in
vitro and in mouse models. El-Deiry said that the discovery of the compound
was a natural extension of his lab's work on understanding tumor-suppressing
pathways downstream of p53. "We got into this in the mid-to-late 1990s
when we discovered that the TRAIL death receptors were regulated by p53, and we
subsequently showed that TRAIL itself is regulated by p53," he
said. "Once we knew that, it became pretty straightforward for us to
conceptualize and go after small molecules that could induce TRAIL
independent of p53."

Oncoceutics
now plans to advance TIC10, which has been renamed ONC201, into a Phase I/II
trial in patients with solid tumors, which will include GBM. The trial is being
funded by a Pennsylvania Department of Health grant to Oncoceutics. "If it
looks safe in the early study, we would like to move into Phase II studies in
combination with other targeted cancer therapies in responsive tumor types,"
El-Deiry said.

He
said his lab will continue to work out the precise mechanism by which TIC10
induces TRAIL expression and kills cancer cells.

"We
are absolutely committed to identifying the precise molecular target,"
El-Deiry said. "We have unpublished evidence that there are some tumor
cell lines that respond to TIC10 as a single agent but not to the combination
of small molecules that target Akt and ERK, and we plan to study this further
to understand why this occurs."

Carl
Ware, professor and director of the Infectious and Inflammatory Disease Center
at the Sanford-Burnham Medical Research Institute, wanted further
confirmation that TIC10's anticancer effects are mediated by TRAIL.

"The
authors provide one experiment utilizing a blocking antibody to TRAIL to
demonstrate that the TIC10-induced apoptosis is TRAIL dependent, but the
experiment was limited to the original tumor line used to screen for TIC,"
said Ware. "The use of this or a similar antibody would provide an
approach to discriminate between TIC10-induced TRAIL expressed in transplanted
human tumors and the bystander effect from TIC10-induced mouse TRAIL. Such
experiments would provide more convincing evidence that TRAIL is involved in
the action of TIC10 in vivo."

Ware's lab is currently focusing on the role TRAIL plays
in the immune system to control viral infection.

Donald Buchsbaum, professor and director of the Division
of Radiation Biology at The University of Alabama at Birmingham,
wanted to see experiments in TRAIL-resistant cells. "It would have been
informative if this paper had reported results for TRAIL-resistant cell lines
and their sensitivity to TIC10," he said. "I believe the major
limitation to successful clinical translation of TRAIL and agonistic death
receptor antibody therapy has been the high incidence of resistance in the
majority of patient tumors due to the overexpression of modulators of
apoptosis."

The University of Alabama at Birmingham is leading a
Phase II trial of Daiichi Sankyo Co. Ltd.'s
DR5-agonist antibody tigatuzumab
with or without Abraxane
nab-paclitaxel in patients with triple-negative breast cancer. Celgene Corp.'s Abraxane is
approved to treat non-small cell lung cancer (NSCLC) and metastatic breast
cancer.

Human Genome Sciences Inc.
had been developing two antibodies before it was acquired by GlaxoSmithKline plc
last year-the DR5 agonist lexatumumab and the DR4
agonist mapatumumab. However, GSK had previously
obtained rights to the programs under a licensing agreement with HGS that GSK
terminated in 2008, calling into question whether the pharma is now interested
in pursuing their development. GSK declined to confirm the programs'
development status.

Genentech
discontinued development of its DR5 agonist antibody RG7425
and recombinant TRAIL in 2009 and currently lists no TRAIL- or death receptor-targeted
drugs in its pipeline. Amgen Inc. declined to confirm
the status of its recombinant TRAIL (dulanermin)
and does not list any TRAIL programs in its pipeline.

Pennsylvania State University has filed a patent
application covering the composition and use of TIC10 to treat cancer, and
Oncoceutics exclusively licensed worldwide rights to the compound.

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